The present invention relates to bicyclic heterocycles of general formula 
the tautomers, the stereoisomers and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases which have valuable pharmacological properties, particularly an inhibitory effect on signal transduction mediated by tyrosine kinases, the use thereof for treating diseases, particularly tumoral diseases, diseases of the lungs and respiratory tract, and the preparation thereof.
In the above general formula I
X denotes a methyne group substituted by a cyano group or a nitrogen atom,
Ra denotes a hydrogen atom or a C1-4-alkyl group,
Rb denotes a phenyl, benzyl, or 1-phenylethyl group wherein the phenyl nucleus in each case is substituted by the groups R1 to R3, whilst
R1 and R2, which may be identical or different, in each case denote a hydrogen, fluorine, chlorine, bromine, or iodine atom,
a C14-alkyl, hydroxy, C1-4-alkoxy, C3-6-cycloalkyl, C4-6-cycloalkoxy, C2-5-alkenyl, or C2-5-alkynyl group,
an aryl, aryloxy, arylmethyl, or arylmethoxy group,
a C3-5-alkenyloxy or C3-5-alkynyloxy group, whilst the unsaturated moiety may not be linked to the oxygen atom,
a C1-4-alkylsulfenyl, C1-4-alkylsulfinyl, C1-4-alkylsulfonyl, C1-4-alkylsulfonyloxy, trifluoromethylsulfenyl, trifluoromethylsulfinyl, or trifluoromethylsulfonyl group,
a methyl or methoxy group substituted by 1 to 3 fluorine atoms, an ethyl or ethoxy group substituted by 1 to 5 fluorine atoms,
a cyano or nitro group or an amino group optionally substituted by one or two C1-4-alkyl groups, whilst the substituents may be identical or different, or
R1 together with R2, if they are bound to adjacent carbon atoms, denote a xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94NHxe2x80x94, or xe2x80x94CHxe2x95x90Nxe2x80x94NHxe2x80x94 group, and
R3 denotes a hydrogen, fluorine, chlorine, or bromine atom,
a C1-4-alkyl, trifluoromethyl, or C1-4-alkoxy group,
Rc denotes a hydrogen atom or a C1-4-alkyl group,
Rd denotes a hydrogen atom, a C1-6-alkoxy, C4-7-cycloalkoxy, or C3-7-cycloalkyl-C1-4-alkoxy group,
a C2-6-alkoxy group, which is substituted from position 2 by a hydroxy, C1-4-alkoxy, C4-7-cycloalkoxy, C3-7-cycloalkyl-C1-3-alkoxy, di-(C1-4-alkyl)-amino, pyrrolidino, piperidino, morpholino, piperazino, or 4-(C1-4-alkyl)piperazino group, whilst the abovementioned cyclic imino groups may be substituted by one or two C1-2-alkyl groups,
a tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy, or tetrahydropyranylmethoxy group,
A denotes a 1,1- or 1,2-vinylene group optionally substituted by a methyl or trifluoromethyl group or by two methyl groups,
a 1,3-butadien-1,4-ylene group optionally substituted by a methyl or trifluoromethyl group or by two methyl groups, or an ethynylene group,
B denotes a C1-6-alkylene group wherein one or two hydrogen atoms may be replaced by fluorine atoms, or, if B is bound to a carbon atom of group C, it may also denote a bond,
C denotes a pyrrolidino group wherein the two hydrogen atoms in the 2 position are replaced by a group D, wherein
D denotes a xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94Oxe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94CH2CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94Oxe2x80x94COxe2x80x94CH2xe2x80x94, or xe2x80x94CH2CH2CH2xe2x80x94Oxe2x80x94COxe2x80x94 bridge optionally substituted by one or two C1-2-alkyl groups,
a pyrrolidino group wherein the two hydrogen atoms in the 3 position are replaced by a group E, wherein
E denotes an xe2x80x94Oxe2x80x94COxe2x80x94CH2CH2xe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94Oxe2x80x94COxe2x80x94, xe2x80x94Oxe2x80x94COxe2x80x94CH2CH2CH2xe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94CH2CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94Oxe2x80x94COxe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2CH2xe2x80x94Oxe2x80x94COxe2x80x94, xe2x80x94Oxe2x80x94COxe2x80x94CH2xe2x80x94NR4xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94CH2xe2x80x94NR4xe2x80x94, xe2x80x94Oxe2x80x94COxe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94, or xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94CH2xe2x80x94Oxe2x80x94 bridge optionally substituted by one or two C1-2-alkyl groups,
whilst R4 denotes a hydrogen atom or a C1-4-alkyl group,
a piperidino or hexahydroazepino group wherein the two hydrogen atoms in the 2 position are replaced by a group D, whilst D is as hereinbefore defined,
a piperidino or hexahydroazepino group wherein the two hydrogen atoms in the 3 position or in the 4 position are replaced by a group E, whilst E is as hereinbefore defined,
a piperazino or 4-(C1-4-alkyl)piperazino group wherein the two hydrogen atoms in the 2 position or in the 3 position of the piperazino ring are replaced by a group D, where D is as hereinbefore defined,
a pyrrolidino or piperidino group wherein two vicinal hydrogen atoms are replaced by an xe2x80x94Oxe2x80x94COxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94, xe2x80x94Oxe2x80x94COxe2x80x94CH2CH2xe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94Oxe2x80x94COxe2x80x94, xe2x80x94Oxe2x80x94COxe2x80x94CH2xe2x80x94NR4xe2x80x94, or xe2x80x94Oxe2x80x94COxe2x80x94CH2xe2x80x94Oxe2x80x94 bridge optionally substituted by one or two C1-2-alkyl groups, whilst R4 is as hereinbefore defined and the heteroatoms of the abovementioned bridges are not bound at the 2 or 5 position of the pyrrolidine ring and are not bound at the 2 or 6 position of the piperidino ring,
a piperazino or 4-(C1-4-alkyl)piperazino group wherein a hydrogen atom in the 2 position together with a hydrogen atom in the 3 position of the piperazino ring are replaced by a xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94CH2xe2x80x94 or xe2x80x94CH2CH2xe2x80x94Oxe2x80x94COxe2x80x94 bridge optionally substituted by one or two C1-2-alkyl groups,
a piperazino group wherein a hydrogen atom in the 3 position together with the hydrogen atom in the 4 position are replaced by a xe2x80x94COxe2x80x94Oxe2x80x94CH2CH2xe2x80x94 or xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94CH2xe2x80x94 bridge optionally substituted by one or two C1-2-alkyl groups, whilst in each case the left-hand end of the abovementioned bridges is bound to the 3 position of the piperazino ring,
a pyrrolidino, piperidino, or hexahydroazepino group substituted by the group R5, wherein
R5 denotes a 2-oxotetrahydrofuranyl, 2-oxotetrahydropyranyl, 2-oxo-1,4-dioxanyl, or 2-oxo-4-(C1-4-alkyl)-morpholinyl group optionally substituted by one or two C1-2-alkyl groups,
a pyrrolidino group substituted in the 3 position by a 2-oxomorpholino group, whilst the 2-oxomorpholino group may be substituted by one or two C1-2-alkyl groups,
a piperidino or hexahydroazepino group substituted in the 3 or 4 position by a 2-oxomorpholino group, whilst the 2-oxomorpholino group may be substituted by one or two CH1-2-alkyl groups,
a 4-(C1-4-alkyl)piperazino or 4-(C1-4-alkyl)-homopiperazino group substituted at a cyclic carbon atom by R5, wherein R5 is as hereinbefore defined,
a piperazino or homopiperazino group substituted in the 4 position by the group R6, wherein
R6 denotes a 2-oxotetrahydrofuran-3-yl, 2-oxotetrahydrofuran-4-yl, 2-oxotetrahydropyran-3-yl, 2-oxotetrahydropyran-4-yl, or 2-oxotetrahydropyran-5-yl group optionally substituted by one or two C1-2-alkyl groups,
a pyrrolidino group substituted in the 3 position by a (R4NR6), R6O, R6S, R6SO, or R6SO2 group, whilst R4 and R6 are as hereinbefore defined,
a piperidino or hexahydroazepino group substituted in the 3 or 4 position by an (R4NR6), R6O, R6S, R6SO, or P6SO2 group wherein R4 and R6 are as hereinbefore defined,
a pyrrolidino, piperidino, or hexahydroazepino group substituted by a R5-C1-4-alkyl, (R4NR6)xe2x80x94C1-4-alkyl, R6Oxe2x80x94C1-4-alkyl, R6Sxe2x80x94C1-4-alkyl, R6SOxe2x80x94C1-4-alkyl, R6SO2xe2x80x94C1-4-alkyl, or R4NR6xe2x80x94CO group wherein R4 to R6 are as hereinbefore defined,
a pyrrolidino group substituted in the 3 position by a R5xe2x80x94COxe2x80x94NR4, R5xe2x80x94C1-4-alkylene-CONR4, (R4NR6)xe2x80x94C1-4-alkylene-CONR4, R6Oxe2x80x94C1-4-alkylene-CONR4, R6Sxe2x80x94C1-4-alkylene-CONR4, R6SOxe2x80x94C1-4-alkylene-CONR4, R6SO2xe2x80x94C1-4-alkylene-CONR4, 2-oxomorpholino-C1-4-alkylene-CONR4, R5xe2x80x94C1-4-alkylene-Y, or C2-4-alkyl-Y group, whilst the C2-4-alkyl moiety of the C2-4-alkyl-Y group is substituted in each case from position 2 by a (R4NR6), R6O, R6S, R6SO, or R6SO2 group and the 2-oxomorpholino moiety may be substituted by one or two C1-2-alkyl groups, wherein
R4 to R6 are as hereinbefore defined, and
Y denotes an oxygen or sulfur atom, an imino, Nxe2x80x94(C1-4-alkyl)-imino, sulfinyl, or sulfonyl group,
a piperidino or hexahydroazepino group substituted in the 3 or 4 position by a R5xe2x80x94COxe2x80x94NR4, R5xe2x80x94C1-4-alkylene-CONR4, (R4NR6)xe2x80x94C1-4-alkylene-CONR4, R6Oxe2x80x94C1-4-alkylene-CONR4, R6Sxe2x80x94C1-4-alkylene-CONR4, R6SOxe2x80x94C1-4-alkylene-CONR4, R6SO2xe2x80x94C1-4-alkylene-CONR4, 2-oxomorpholino-C1-4-alkylene-CONR4, R5xe2x80x94C1-4-alkylene-Y, or C2-4-alkyl-Y group wherein Y is as hereinbefore defined, the 2-oxomorpholino moiety may be substituted by one or two C1-2-alkyl groups and the C2-4-alkyl moiety of the C2-4-alkyl-Y group is substituted in each case from position 2 by a (R4NR6), R6O, R6S, R6SO, or R6SO2 group, whilst R4 to R6 are as hereinbefore defined,
a 4-(C1-4-alkyl)piperazino or 4-(C1-4-alkyl)-homopiperazino group substituted at a cyclic carbon atom by an R5xe2x80x94C1-4-alkyl, (R4NR6)xe2x80x94C1-4-alkyl, R6xe2x80x94C1-4-alkyl, R6Sxe2x80x94C1-4-alkyl, R6SOxe2x80x94C1-4-alkyl, R6SO2xe2x80x94C1-4-alkyl, or R4NR6xe2x80x94CO group, wherein R4 to R6 are as hereinbefore defined,
a piperazino or homopiperazino group substituted in the 4 position by an R5xe2x80x94C1-4-alkyl, R5xe2x80x94CO, R5xe2x80x94C1-4-alkylene-CO, (R4NR6)xe2x80x94C1-4-alkylene-CO, R6Oxe2x80x94C1-4-alkylene-CO, R6Sxe2x80x94C1-4-alkylene-CO, R6SOxe2x80x94C1-4-alkylene-CO, or R6SO2xe2x80x94C1-4-alkylene-CO group wherein R4 to R6 are as hereinbefore defined,
a piperazino or homopiperazino group substituted in the 4 position by a C2-4-alkyl group, wherein the C2-4-alkyl group is substituted in each case from position 2 by an (R4NR6), R6O, R6S, R6SO, or R6SO2 group, whilst R4 and R6 are as hereinbefore defined,
a pyrrolidino, piperidino, or hexahydroazepino group substituted by a 2-oxomorpholino-C1-4-alkyl group, wherein the 2-oxomorpholino moiety may be substituted by one or two C1-2-alkyl groups,
a pyrrolidino group substituted in the 3 position by a C2-4-alkyl-Y group, wherein Y is as hereinbefore defined and the C2-4-alkyl moiety of the C2-4-alkyl-Y group is substituted in each case from position 2 by a 2-oxomorpholino group optionally substituted by one or two C1-2-alkyl groups,
a piperidino or hexahydroazepino group substituted in the 3 or 4 position by a C2-4-alkyl-Y group wherein Y is as hereinbefore defined and the C2-4-alkyl moiety of the C2-4-alkyl-Y group is substituted in each case from position 2 by a 2-oxomorpholino group optionally substituted by one or two C1-2-alkyl groups,
a 4-(C1-4-alkyl)piperazino or 4-(C1-4-alkyl)-homopiperazino group substituted at a cyclic carbon atom by a 2-oxomorpholino-C1-4-alkyl group, wherein the 2-oxomorpholino moiety may be substituted by one or two C1-2-alkyl groups,
a piperazino or homopiperazino group substituted in the 4 position by a 2-oxomorpholino-C1-4-alkylene-CO group, wherein the 2-oxomorpholino moiety may be substituted by one or two C1-2-alkyl groups,
a piperazino or homopiperazino group substituted in the 4 position by a C2-4-alkyl group, wherein the C2-4-alkyl moiety is substituted in each case from position 2 by a 2-oxomorpholino group optionally substituted by one or two C1-2-alkyl groups,
a pyrrolidinyl or piperidinyl group substituted in the 1 position by the group R6, by an R5xe2x80x94C1-4-alkyl, R513 CO, R5xe2x80x94C1-4-alkylene-CO, (R4NR6)xe2x80x94C1-4-alkylene-CO, R6Oxe2x80x94C1-4-alkylene-CO, R6Sxe2x80x94C1-4-alkylene-CO, R6SOxe2x80x94C1-4-alkylene-CO, R6SO2xe2x80x94C1-4-alkylene-CO, or 2-oxomorpholino-C1-4-alkylene-CO group wherein R4 to R6 are as hereinbefore defined and the 2-oxomorpholino moiety may be substituted by one or two C1-2-alkyl groups,
a pyrrolidinyl or piperidinyl group substituted in the 1 position by a C2-4-alkyl group wherein the C2-4-alkyl moiety is substituted in each case from position 2 by an (R4NR6), R6O, R6S, R6SO, R6SO2, or 2-oxomorpholino group, whilst R4 and R6 are as hereinbefore defined and the 2-oxomorpholino moiety may be substituted by one or two C1-2-alkyl groups,
a pyrrolidin-3-yl-NR4, piperidin-3-yl-NR4, or piperidin-4-yl-NR4 group substituted in each case at the cyclic nitrogen atom by the group R6, by an R5xe2x80x94C1-4-alkyl, R5xe2x80x94CO, R5xe2x80x94C1-4-alkylene-CO, (R4NR6)xe2x80x94C1-4-alkylene-CO, R6Oxe2x80x94C1-4-alkylene-CO, R6Sxe2x80x94C1-4-alkylene-CO, R6SOxe2x80x94C1-4-alkylene-CO, R6SO2xe2x80x94C1-4-alkylene-CO, or 2-oxomorpholino-C1-4-alkylene-CO group, wherein R4 to R6 are as hereinbefore defined and the 2-oxomorpholino moiety may be substituted by one or two C1-2-alkyl groups,
a pyrrolidin-3-yl-NR4, piperidin-3-yl-NR4, or piperidin-4-yl-NR4 group substituted in each case at the cyclic nitrogen atom by a C2-4-alkyl group, wherein the C2-4-alkyl moiety is substituted in each case from position 2 by an (R4NR6), R6O, R6S, R6SO, R6SO2, or 2-oxomorpholino group, whilst R4 and R6 are as hereinbefore defined and the 2-oxomorpholino moiety may be substituted by one or two C1-2-alkyl groups,
a R5xe2x80x94C1-4-alkylene-NR4 group wherein R4 and R5 are as hereinbefore defined, or
a C2-4-alkyl-NR4-group, wherein the C2-4-alkyl moiety is substituted in each case from position 2 by an (R4NR6), R6O, R6S, R6SO, R6SO2, or 2-oxomorpholino group, whilst R4 and R6 are as hereinbefore defined and the 2-oxomorpholino moiety may be substituted by one or two C1-2-alkyl groups, while
by the abovementioned aryl moieties is meant a phenyl group which may in each case be mono- or disubstituted by Rxe2x80x2, while the substituents may be identical or different and
Rxe2x80x2 denotes a fluorine, chlorine, bromine, or iodine atom, a C1-2-alkyl, trifluoromethyl, or C1-2-alkoxy group or
two groups Rxe2x80x2, if they are bound to adjacent carbon atoms, together denote a C3-4-alkylene, methylenedioxy, or 1,3-butadien-1,4-ylene group.
Preferred compounds of the above general formula I are those wherein
X denotes a nitrogen atom,
Ra denotes a hydrogen atom,
Rb denotes a phenyl, benzyl, or 1-phenylethyl group wherein the phenyl nucleus is substituted in each case by the groups R1 to R3, whilst
R1 and R2, which may be identical or different, in each case denote a methyl group or a hydrogen, fluorine, chlorine, or bromine atom and
R3 denotes a hydrogen atom,
Rc denotes a hydrogen atom,
Rd denotes a hydrogen atom, a methoxy, ethoxy, C4-6-cycloalkoxy, C3-6-cycloalkylmethoxy, 2-methoxyethoxy, 2-(cyclobutyloxy)ethoxy, 2-(cyclopentyloxy)ethoxy, 2-(cyclohexyloxy)ethoxy, 2-(cyclopropylmethoxy)ethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuran-2-ylmethoxy, tetrahydrofuran-3-ylmethoxy, tetrahydropyran-2-ylmethoxy, or tetrahydropyran-4-ylmethoxy group,
A denotes a 1,2-vinylene group,
B denotes a methylene or ethylene group or, if B is bound to a carbon atom of group C, it may also denote a bond,
C denotes a pyrrolidino group wherein the two hydrogen atoms in the 3 position are replaced by a group E, wherein
E denotes a xe2x80x94Oxe2x80x94COxe2x80x94CH2CH2xe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94Oxe2x80x94COxe2x80x94, xe2x80x94CH2CH2xe2x80x94Oxe2x80x94COxe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94COxe2x80x94CH2xe2x80x94NR4xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94CH2xe2x80x94NR4xe2x80x94, xe2x80x94Oxe2x80x94COxe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94, or xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94CH2xe2x80x94Oxe2x80x94 bridge optionally substituted by one or two methyl groups,
where R4 denotes a methyl or ethyl group,
a piperidino group wherein the two hydrogen atoms in the 3 position or in the 4 position are replaced by a group E, where E is as hereinbefore defined,
a pyrrolidino or piperidino group wherein two vicinal hydrogen atoms are replaced by an xe2x80x94Oxe2x80x94COxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94, xe2x80x94Oxe2x80x94COxe2x80x94CH2xe2x80x94NR4xe2x80x94, or xe2x80x94Oxe2x80x94COxe2x80x94CH2xe2x80x94Oxe2x80x94 bridge optionally substituted by one or two methyl groups, whilst R4 is as hereinbefore defined and the heteroatoms of the abovementioned bridges are not bound at the 2 or 5 position of the pyrrolidine ring and are not bound at the 2 or 6 position of the piperidino ring,
a piperazino group wherein a hydrogen atom in the 3 position together with the hydrogen atom in the 4 position are replaced by a xe2x80x94COxe2x80x94Oxe2x80x94CH2CH2xe2x80x94 or xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94CH2xe2x80x94 bridge optionally substituted by one or two methyl groups, whilst in each case the left-hand end of the abovementioned bridges is bound to the 3 position of the piperazino ring,
a pyrrolidino or piperidino group substituted by the group R5, wherein
R5 denotes a 2-oxotetrahydrofuranyl, 2-oxo-1,4-dioxanyl, or 2-oxo-4-(C1-4-alkyl)-morpholinyl group optionally substituted by one or two methyl groups,
a pyrrolidino group substituted in the 3 position by a 2-oxomorpholino group, whilst the 2-oxomorpholino group may be substituted by one or two methyl groups,
a piperidino group substituted in the 3 or 4 position by a 2-oxomorpholino group, whilst the 2-oxomorpholino group may be substituted by one or two methyl groups,
a piperazino group substituted in the 4 position by the group R6, wherein
R6 denotes a 2-oxotetrahydrofuran-3-yl or 2-oxotetrahydrofuran-4-yl group optionally substituted by one or two methyl groups,
a pyrrolidino group substituted in the 3 position by an (R4NR6), R6O, R6S, R6SO, or R6SO2 group, whilst R4 and R6 are as hereinbefore defined,
a piperidino group substituted in the 3 or 4 position by an (R4NR6), R6O, R6S, R6SO, or R6SO2 group, whilst R4 and R6 are as hereinbefore defined,
a pyrrolidino or piperidino group substituted by an (R4NR6)xe2x80x94C1-2-alkyl, HNR6xe2x80x94CO, or R4NR6xe2x80x94CO group, whilst R4 and R6 are as hereinbefore defined,
a pyrrolidino group substituted in the 3 position by an R5xe2x80x94COxe2x80x94NH or R5xe2x80x94COxe2x80x94NR4 group, whilst R4 and R5 are as hereinbefore defined,
a piperidino group substituted in the 3 or 4 position by an R5xe2x80x94COxe2x80x94NH or R5xe2x80x94COxe2x80x94NR4 group, whilst R4 and R5 are as hereinbefore defined,
a piperazino group substituted in the 4 position by an R5xe2x80x94C1-2-alkyl, R5xe2x80x94CO, R5xe2x80x94C1-2-alkylene-CO, (R4NR6)xe2x80x94C1-2-alkylene-CO, R6Oxe2x80x94C1-2-alkylene-CO, R6Sxe2x80x94C1-2-alkylene-CO, R6SOxe2x80x94C1-2-alkylene-CO, or R6SO2xe2x80x94C1-2-alkylene-CO group wherein R4 to R6 are as hereinbefore defined,
a piperazino group substituted in the 4 position by a C2-3-alkyl group wherein the C2-3-alkyl group is substituted in each case from position 2 by an (R4NR6), R6O, R6S, R6SO, or R6SO2 group, where R4 and R6 are as hereinbefore defined,
a pyrrolidino or piperidino group substituted by a 2-oxomorpholino-C1-2-alkyl group wherein the 2-oxomorpholino moiety may be substituted by one or two methyl groups,
a piperazino group substituted in the 4 position by a 2-oxomorpholino-C1-2-alkylene-CO group wherein the 2-oxomorpholino moiety may be substituted by one or two methyl groups,
a piperazino group substituted in the 4 position by a C2-3-alkyl group wherein the C2-3-alkyl moiety is substituted in each case from position 2 by a 2-oxomorpholino group optionally substituted by one or two methyl groups,
a piperidinyl group substituted in the 1 position by the group R6, by an R5xe2x80x94C1-2-alkyl, R5xe2x80x94CO, R5xe2x80x94C1-2-alkylene-CO, (R4NR6)xe2x80x94C1-2-alkylene-CO, R6Oxe2x80x94C1-2-alkylene-CO, R6Sxe2x80x94C1-2-alkylene-CO, R6SOxe2x80x94C1-2-alkylene-CO, R6SO2xe2x80x94C1-2-alkylene-CO, or 2-oxomorpholino-C1-2-alkylene-CO group, whilst R4 to R6 are as hereinbefore defined and the 2-oxomorpholino moiety may be substituted by one or two methyl groups,
a piperidinyl group substituted in the 1 position by a C2-3-alkyl group wherein the C2-3-alkyl moiety is substituted in each case from position 2 by an (R4NR6), R6O, R6S, R6SO, R6SO2, or 2-oxomorpholino group, whilst R4 and R6 are as hereinbefore defined and the 2-oxomorpholino moiety may be substituted by one or two methyl groups,
a pyrrolidin-3-yl-NR4, piperidin-3-yl-NR4, or piperidin-4-yl-NR4 group substituted in each case at the cyclic nitrogen atom by the group R6, by an R5xe2x80x94C1-2-alkyl, R5xe2x80x94CO, R5xe2x80x94C1-2-alkylene-CO, (R4NR6)xe2x80x94C1-2-alkylene-CO, R6Oxe2x80x94C1-2-alkylene-CO, R6Sxe2x80x94C1-2-alkylene-CO, R6SOxe2x80x94C1-2-alkylene-CO, R6SO2xe2x80x94C1-2-alkylene-CO, or 2-oxomorpholino-C1-2-alkylene-CO group, wherein R4 to R6 are as hereinbefore defined and the 2-oxomorpholino moiety may be substituted by one or two methyl groups, or
a pyrrolidin-3-yl-NR4, piperidin-3-yl-NR4, or piperidin-4-yl-NR4 group substituted in each case at the cyclic nitrogen atom by a C2-3-alkyl group, wherein the C2-3-alkyl moiety is substituted in each case from position 2 by an (R4NR6), R6O, R6S, R6SO, R6SO2, or 2-oxomorpholino group, whilst R4 and R6 are as hereinbefore defined and the 2-oxomorpholino moiety may be substituted by one or two methyl groups,
the tautomers, the stereoisomers and the salts thereof.
Particularly preferred compounds of general formula I are those wherein
X denotes a nitrogen atom,
Ra denotes a hydrogen atom,
Rb denotes a phenyl, benzyl, or 1-phenylethyl group wherein the phenyl nucleus is substituted in each case by the groups R1 to R3, whilst
R1 and R2, which may be identical or different, each denote a methyl group or a hydrogen, fluorine, chlorine, or bromine atom and
R3 denotes a hydrogen atom,
Rc denotes a hydrogen atom,
Rd denotes a hydrogen atom, a methoxy, ethoxy, C4-6-cycloalkoxy, C3-6-cycloalkylmethoxy, 2-methoxyethoxy, 2-(cyclobutyloxy)ethoxy, 2-(cyclopentyloxy)ethoxy, 2-(cyclohexyloxy)ethoxy, 2-(cyclopropylmethoxy)ethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuran-2-ylmethoxy, tetrahydrofuran-3-ylmethoxy, tetrahydropyran-2-ylmethoxy, or tetrahydropyran-4-ylmethoxy group,
A denotes a 1,2-vinylene group,
B denotes a methylene or ethylene group or, if B is bound to a carbon atom of group C, it may also denote a bond,
C denotes a piperidino group wherein the two hydrogen atoms in the 4 position are replaced by a xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94Oxe2x80x94COxe2x80x94, xe2x80x94CH2CH2xe2x80x94Oxe2x80x94COxe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94COxe2x80x94CH2xe2x80x94NCH3xe2x80x94CH2xe2x80x94, or xe2x80x94Oxe2x80x94COxe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94 bridge,
a piperazino group wherein a hydrogen atom in the 3 position together with the hydrogen atom in the 4 position are replaced by a xe2x80x94COxe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94CH2xe2x80x94 bridge, whilst in each case the left-hand end of the above bridges is bound to the 3 position of the piperazino ring,
a piperidino group substituted by a 2-oxotetrahydrofuranyl group,
a piperidino group which is substituted in the 4 position by a 2-oxomorpholino or 2-oxomorpholinomethyl group, whilst the 2-oxomorpholino moiety may in each case be substituted by one or two methyl groups,
a piperazino group which is substituted in the 4 position by a 2-oxotetrahydrofuran-3-yl or 2-oxotetrahydrofuran-4-yl group,
a piperidino group which is substituted in the 4 position by a CH3NR6 or R6S group, whilst
R6 denotes a 2-oxotetrahydrofuran-3-yl or 2-oxotetrahydrofuran-4-yl group,
a piperazino group which is substituted in the 4 position by a 2-oxotetrahydrofuranylmethyl or 2-oxotetrahydrofuranyl-carbonyl group,
a piperazino group which is substituted in the 4 position by a straight-chained C2-3-alkyl group, whilst the C2-3-alkyl moiety is terminally substituted in each case by a 2-oxotetrahydrofuran-3-ylsulfenyl group,
a piperidin-4-yl group which is substituted in the 1 position by a 2-oxotetrahydrofuran-3-yl or 2-oxotetrahydrofuran-4-yl group, or
a piperidin-4-yl-NCH3 group which is substituted at the cyclic nitrogen atom by a 2-oxotetrahydrofuran-3-yl, 2-oxotetrahydrofuran-4-yl, or 2-oxotetrahydrofuranylcarbonyl group,
the tautomers, the stereoisomers and the salts thereof.
Most especially preferred compounds of the above general formula I are those wherein
X denotes a nitrogen atom,
Ra denotes a hydrogen atom, Rb denotes a 1-phenylethyl group or a phenyl group substituted by the groups R1 to R3, wherein
R1 and R2, which may be identical or different, each denote a methyl group or a hydrogen, fluorine, chlorine, or bromine atom and
R3 denotes a hydrogen atom,
Rc denotes a hydrogen atom,
Rd denotes a hydrogen atom, a methoxy, ethoxy, 2-methoxy-ethoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, or tetrahydrofuran-2-ylmethoxy group,
A denotes a 1,2-vinylene group,
B denotes a methylene group or, if B is bound to a carbon atom of group C, it may also denote a bond,
C denotes a piperidino group in which the two hydrogen atoms are replaced in the 4 position by a xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94Oxe2x80x94COxe2x80x94, xe2x80x94CH2CH2xe2x80x94Oxe2x80x94COxe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94COxe2x80x94CH2xe2x80x94NCH3xe2x80x94CH2xe2x80x94, or xe2x80x94Oxe2x80x94COxe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94 bridge,
a piperazino group wherein a hydrogen atom in the 3 position together with the hydrogen atom in the 4 position are replaced by a xe2x80x94COxe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94CH2xe2x80x94 bridge, while in each case the left-hand end of the abovementioned bridges is bound to the 3 position of the piperazino ring,
a piperidino group substituted by a 2-oxotetrahydrofuranyl group,
a piperidino group which is substituted in the 4 position by a 2-oxomorpholino or 2-oxomorpholinomethyl group, while the 2-oxomorpholino moiety may in each case be substituted by one or two methyl groups,
a piperazino group which is substituted in the 4 position by a 2-oxotetrahydrofuran-3-yl or 2-oxotetrahydrofuran-4-yl group,
a piperidino group which is substituted in the 4 position by a CH3NR6 or R6S group, where
R6 denotes a 2-oxotetrahydrofuran-3-yl or 2-oxotetrahydrofuran-4-yl group,
a piperazino group which is substituted in the 4 position by a 2-oxotetrahydrofuranylmethyl or 2-oxotetrahydrofuranylcarbonyl group,
a piperazino group which is substituted in the 4 position by a [2-(2-oxotetrahydrofuran-3-ylsulfenyl)ethyl] group,
a piperidin-4-yl group which is substituted in the 1 position by a 2-oxotetrahydrofuran-3-yl or 2-oxotetrahydrofuran-4-yl group, or
a piperidin-4-yl-NCH3 group which is substituted at the cyclic nitrogen atom by a 2-oxotetrahydrofuran-3-yl, 2-oxotetrahydrofuran-4-yl, or 2-oxotetrahydrofuranylcarbonyl group,
the tautomers, the stereoisomers and the salts thereof.
The following are mentioned as most particularly preferred compounds of general formula I:
(a) 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[4-(2-oxotetrahydrofuran-3-yl)piperazin-1-yl]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline,
(b) 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[4-(2-oxotetrahydrofuran-4-yl)piperazin-1-yl]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline,
(c) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(4-{2-[(2-oxotetrahydrofuran-3-yl)sulfanyl]ethyl}piperazin-1-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline,
(d) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(3-oxoperhydropyrazino[2,1-c][1,4]oxazin-8-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline,
(e) (S)-4-[(3-chloro-4-fluorophenyl)amino]-6-[(4-{4-[(5-oxotetrahydrofuran-2-yl)carbonyl]piperazin-1-yl}-1-oxo-2-buten-1-yl)amino]-7-cyclopropylmethoxyquinazoline,
(f) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(1-oxoperhydropyrazino[2,1-c][1,4]oxazin-8-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline and
(g) 4-[(3-chloro-4-fluorophenyl)amino]-6-[(4-{4-[(2-oxotetrahydrofuran-3-yl)sulfanyl]piperidin-1-yl}-1-oxo-2-buten-1-yl)amino]-7-cyclopropylmethoxyquinazoline
and the salts thereof.
The compounds of general formula I may be prepared, for example, by the following methods:
A. Reacting a Compound of General Formula 
wherein:
Ra to Rd and X are as hereinbefore defined,
with a compound of general formula
HOxe2x80x94COxe2x80x94Axe2x80x94Bxe2x80x94Cxe2x80x83xe2x80x83(III)
xe2x80x83wherein
A to C are as hereinbefore defined, or with the reactive derivatives thereof.
The reaction is optionally carried out in a solvent or mixture of solvents such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, or dioxane, optionally in the presence of a dehydrating agent, e.g., in the presence of isobutyl chloroformate, thionyl chloride, trimethyl chlorosilane, phosphorus trichloride, phosphorus pentoxide, N,Nxe2x80x2-dicyclohexylcarbodiimide, N,Nxe2x80x2-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,Nxe2x80x2-carbonyldiimidazole, triphenylphosphine/carbon tetrachloride, or O-(benzotriazol-1-yl)-N,N,Nxe2x80x2,Nxe2x80x2-tetramethyluronium tetrafluoroborate, or with a corresponding reactive derivative such as a corresponding ester, acid halide, or anhydride, optionally with the addition of an inorganic or organic base, preferably with the addition of an organic base such as triethylamine, N-ethyldiisopropylamine, or 4-dimethylaminopyridine, conveniently at temperatures between 0xc2x0 C. and 150xc2x0 C., preferably at temperatures between 0xc2x0 C. and 80xc2x0 C.
b. Reacting a Compound of General Formula 
optionally formed in the reaction mixture, wherein
Ra to Rd, A, B, and X are as hereinbefore defined, and
Z1, denotes an exchangeable group such as a halogen atom or a substituted sulfinyl or sulfonyl group, e.g., a chlorine or bromine atom, a methylsulfinyl, propylsulfinyl, phenylsulfinyl, benzylsulfinyl, methylsulfonyl, propylsulfonyl, phenylsulfonyl, or benzylsulfonyl group,
with a compound of general formula
Hxe2x80x94Gxe2x80x83xe2x80x83(V)
xe2x80x83wherein
G denotes one of the groups mentioned for C hereinbefore which is linked to the group B via a nitrogen atom.
However, G may also denote a group which can be converted by lactonization into one of the groups mentioned for C hereinbefore, which are linked to the group B via a nitrogen atom (e.g., a correspondingly substituted gamma- or delta-hydroxycarboxylic acid ester group).
The reaction is conveniently carried out in a solvent such as isopropanol, butanol, tetrahydrofuran, dioxane, toluene, chlorobenzene, dimethylformamide, dimethylsulfoxide, methylene chloride, ethylene glycol monomethylether, ethylene glycol diethylether, or sulfolane, optionally in the presence of an inorganic or tertiary organic base, e.g., sodium carbonate or potassium hydroxide, a tertiary organic base, e.g., triethylamine, or in the presence of N-ethyldiisopropylamine (Hxc3xcnig base), whilst these organic bases may simultaneously serve as the solvent, and optionally in the presence of a reaction accelerator such as an alkali metal halide at temperatures between xe2x88x9220xc2x0 C. and 150xc2x0 C., but preferably at temperatures between xe2x88x9210xc2x0 C. and 100xc2x0 C. The reaction may, however, also be carried out without a solvent or in an excess of the compound of general formula V used.
If G denotes a group which can be converted by lactonization into one of the groups mentioned for C hereinbefore which are linked to the group B via a nitrogen atom, cyclization to form the corresponding lactone may optionally follow. The cyclization to form the corresponding lactone is optionally carried out in a solvent such as acetonitrile, methylene chloride, tetrahydrofuran, dioxane, or toluene in the presence of an acid such as hydrochloric acid, p-toluenesulfonic acid, or trifluoroacetic acid at temperatures of between xe2x88x9210xc2x0 C. and 120xc2x0 C.
c. In order to prepare a compound of general formula I wherein C denotes one of the groups mentioned for C hereinbefore which contains an imino or HNR4 group substituted by R6 or by an R5-C1-4-alkyl group wherein R4 to R6 are as hereinbefore defined:
Reacting a Compound of General Formula 
wherein
Ra to Rd, A, and B are as hereinbefore defined, and
Cxe2x80x2 denotes one of the groups mentioned for C hereinbefore which contains a corresponding unsubstituted imino or HNR4 group, where R4 is as hereinbefore defined,
with a compound of general formula
Z2xe2x80x94Uxe2x80x83xe2x80x83(VII)
xe2x80x83wherein:
U denotes the group R6 or a R5-C1-4-alkyl group, where R5 and R6 are as hereinbefore defined, and
Z2 denotes an exchangeable group such as a halogen atom or a substituted sulfonyloxy group, e.g., a chlorine or bromine atom, a methylsulfonyloxy, propylsulfonyloxy, phenylsulfonyloxy, or benzylsulfonyloxy group, or
Z2 together with an adjacent hydrogen atom denotes another carbon-carbon bond which is attached to a carbonyl group.
The reaction is conveniently carried out in a solvent such as methanol, ethanol, isopropanol, or acetonitrile and optionally in the presence of a base such as triethylamine, N-ethyldiisopropylamine, or 2-dimethylaminopyridine at temperatures between 0xc2x0 C. and 100xc2x0 C., but preferably at the boiling temperature of the reaction mixture.
If in a compound of general formula VII Z2 denotes an exchangeable group, the reaction is preferably performed in a solvent or mixture of solvents such as methylene chloride, dimethylformamide, dimethylsulfoxide, sulfolane, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran, or dioxane, conveniently in the presence of a tertiary organic base such as triethylamine or N-ethyldiisopropylamine (Hxc3xcnig base), whilst these organic bases may simultaneously serve as the solvent, or in the presence of an inorganic base such as sodium carbonate, potassium carbonate, or sodium hydroxide solution, conveniently at temperatures between xe2x88x9220xc2x0 C. and 200xc2x0 C., preferably at temperatures between 0xc2x0 C. and 150xc2x0 C., or
if in a compound of general formula VII Z2 together with an adjacent hydrogen atom denotes another carbon-carbon bond attached to a carbonyl group, the reaction is preferably carried out in a solvent such as methanol, ethanol, isopropanol, or acetonitrile at temperatures between 0xc2x0 C. and 100xc2x0 C., but preferably at temperatures between 20xc2x0 C. and the boiling temperature of the reaction mixture.
d. In order to prepare a compound of general formula I wherein C denotes one of the groups mentioned for C hereinbefore which contains an imino or HNR4 group substituted by an R5CO, R5xe2x80x94C1-4-alkylene-CO, (R4NR6)xe2x80x94C1-4-alkylene-CO, R6Oxe2x80x94C1-4-alkylene-CO, R6Sxe2x80x94C1-4-alkylene-CO, R6SOxe2x80x94C1-4-alkylene-CO, R6SO2xe2x80x94C1-4-alkylene-CO, or 2-oxomorpholino-C1-4-alkylene-CO group, where R4 to R6 are as hereinbefore defined and the 2-oxomorpholino moiety may be substituted by one or two C1-2-alkyl groups:
Reacting a Compound of General Formula 
wherein
Ra to Rd, A, and B are as hereinbefore defined, and
Cxe2x80x2 denotes one of the groups mentioned for C hereinbefore which contains a corresponding unsubstituted imino or HNR4 group, where R4 is as hereinbefore defined,
with a compound of general formula
HOxe2x80x94COxe2x80x94Wxe2x80x83xe2x80x83(VIII)
xe2x80x83wherein
W denotes the group R5 or a R5xe2x80x94C1-4-alkyl, (R4NR6)xe2x80x94C1-4-alkyl, R6Oxe2x80x94C1-4-alkyl, R6Sxe2x80x94C1-4-alkyl, R6SOxe2x80x94C1-4-alkyl, R6SO2xe2x80x94C1-4-alkyl, or 2-oxomorpholino-C1-4-alkyl group, wherein R4 to R6 are as hereinbefore defined and the 2-oxomorpholino moiety may be substituted by one or two C1-2-alkyl groups.
The reaction is optionally carried out in a solvent or mixture of solvents such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, or dioxane, optionally in the presence of a dehydrating agent, e.g., in the presence of isobutyl chloroformate, thionyl chloride, trimethyl chlorosilane, phosphorus trichloride, phosphorus pentoxide, N,Nxe2x80x2-dicyclohexylcarbodiimide, N,Nxe2x80x2-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,Nxe2x80x2-carbonyldiimidazole, triphenylphosphine/carbon tetrachloride, or O-(benzotriazol-1-yl)-N,N,Nxe2x80x2,Nxe2x80x2-tetramethyluronium tetrafluoroborate, or with a corresponding reactive derivative such as a corresponding ester, acid halide, or anhydride, optionally with the addition of an inorganic or organic base, preferably with the addition of an organic base such as triethylamine, N-ethyldiisopropylamine, or 4-dimethylaminopyridine, conveniently at temperatures between 0xc2x0 C. and 150xc2x0 C., preferably at temperatures between 0xc2x0 C. and 80xc2x0 C.
In the reactions described hereinbefore, any reactive groups present such as hydroxy, carboxy, amino, alkylamino, or imino groups may be protected during the reaction by conventional protecting groups which are cleaved again after the reaction.
For example, a protecting group for a hydroxy group may be a trimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert-butyl, trityl, benzyl, or tetrahydropyranyl group,
protecting groups for a carboxy group may be a trimethylsilyl, methyl, ethyl, tert-butyl, benzyl, or tetrahydropyranyl group, and
protecting groups for an amino, alkylamino, or imino group may be a formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxy-benzyl, or 2,4-dimethoxybenzyl group and additionally, for the amino group, a phthalyl group.
Any protecting group used is optionally subsequently cleaved for example by hydrolysis in an aqueous solvent, e.g., in water, isopropanol/water, acetic acid/water, tetrahydrofuran/water, or dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, or sulfuric acid, or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide, or aprotically, e.g., in the presence of iodotrimethylsilane, at temperatures between 0xc2x0 C. and 120xc2x0 C., preferably at temperatures between 10xc2x0 C. and 100xc2x0 C.
However, a benzyl, methoxybenzyl, or benzyloxycarbonyl group is cleaved, for example, hydrogenolytically, e.g., with hydrogen in the presence of a catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol, ethyl acetate, or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0xc2x0 C. and 100xc2x0 C., but preferably at room temperatures between 20xc2x0 C. and 60xc2x0 C., and at a hydrogen pressure of 1 to 7 bar, but preferably 3 to 5 bar. A 2,4-dimethoxybenzyl group, however, is preferably cleaved in trifluoroacetic acid in the presence of anisole.
A tert-butyl or tert-butyloxycarbonyl group is preferably cleaved by treating with an acid such as trifluoroacetic acid or hydrochloric acid or by treating with iodotrimethylsilane optionally using a solvent such as methylene chloride, dioxane, methanol, or diethyl ether.
A trifluoroacetyl group is preferably cleaved by treating with an acid such as hydrochloric acid, optionally in the presence of a solvent such as acetic acid at temperatures between 50xc2x0 C. and 120xc2x0 C. or by treating with sodium hydroxide solution optionally in the presence of a solvent such as tetrahydrofuran at temperatures between 0xc2x0 C. and 50xc2x0 C.
A phthalyl group is preferably cleaved in the presence of hydrazine or a primary amine such as methylamine, ethylamine, or n-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene/water, or dioxane at temperatures between 20xc2x0 C. and 50xc2x0 C.
Moreover, the compounds of general formula I obtained may be resolved into their enantiomers and/or diastereomers, as mentioned hereinbefore. Thus, for example, cis/trans mixtures may be resolved into their cis and trans isomers, and compounds with at least one optically active carbon atom may be separated into their enantiomers.
Thus, for example, the cis/trans mixtures may be resolved by chromatography into the cis and trans isomers thereof, the compounds of general formula I obtained which occur as racemates may be separated by methods known per se (cf N. L. Allinger and E. L. Eliel in xe2x80x9cTopics in Stereochemistryxe2x80x9d, Vol. 6, Wiley Interscience, 1971) into their optical antipodes and compounds of general formula I with at least 2 asymmetric carbon atoms may be resolved into their diastereomers on the basis of their physical-chemical differences using methods known per se, e.g., by chromatography and/or fractional crystallization, and, if these compounds are obtained in racemic form, they may subsequently be resolved into the enantiomers as mentioned above.
The enantiomers are preferably separated by column separation on chiral phases or by recrystallization from an optically active solvent or by reacting with an optically active substance which forms salts or derivatives such as e.g., esters or amides with the racemic compound, particularly acids and the activated derivatives or alcohols thereof, and separating the diastereomeric mixture of salts or derivatives thus obtained, e.g., on the basis of their differences in solubility, whilst the free antipodes may be released from the pure diastereomeric salts or derivatives by the action of suitable agents. Optically active acids in common use are e.g., the D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid. An optically active alcohol may be for example (+) or (xe2x88x92)-menthol and an optically active acyl group in amides, for example, may be a (+)-or (xe2x88x92)-menthyloxycarbonyl.
Furthermore, the compounds of formula I obtained may be converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts with inorganic or organic acids. Acids which may be used for this purpose include for example hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, or maleic acid.
The compounds of general formulae II to VIII used as starting materials are known from the literature in some cases or may be obtained by methods known from the literature (cf. Examples I to XV).
As already mentioned hereinbefore, the compounds of general formula I according to the invention and the physiologically acceptable salts thereof have valuable pharmacological properties, particularly an inhibiting effect on signal transduction mediated by the Epidermal Growth Factor receptor (EGF-R), whilst this may be achieved for example by inhibiting ligand bonding, receptor dimerization or tyrosine kinase itself. It is also possible that the transmission of signals to components located further along is blocked.
The biological properties of the new compounds were investigated as follows:
The inhibition of the EGF-R-mediated signal transmission can be demonstrated, e.g., with cells which express human EGF-R and whose survival and proliferation depend on stimulation by EGF or TGF-alpha. A cell line of murine origin dependent on interleukin-3-(IL-3) which was genetically modified to express functional human EGF-R was used here. The proliferation of these cells known as F/L-HERc can therefore be stimulated either by murine IL-3 or by EGF (cf. T. von Rxc3xciden et al. in EMBO J. 7, 2749-2756 (1988) and J. H. Pierce et al. in Science 239, 628-631 (1988)).
The starting material used for the F/L-HERc cells was the cell line FDC-P1, the production of which has been described by T. M. Dexter et al., J. Exp. Med. 152 1036-1047 (1980). Alternatively, however, other growth-factor-dependent cells may also be used (cf., e.g., J. H. Pierce et al., Science 239, 628-631 (1988); H. Shibuya et al., Cell 70, 57-67 (1992); and W. S. Alexander et al., EMBO J. 10, 3683-3691 (1991)). For expressing the human EGF-R cDNA (cf. A. Ullrich et al., Nature 309, 418-425 (1984)) recombinant retroviruses were used as described by T. von Rxc3xciden et al., EMBO J. 7, 2749-2756 (1988), except that the retroviral vector LXSN (cf. A. D. Miller et al., BioTechniques 7, 980-990 (1989)) was used for the expression of the EGF-R cDNA and the line GP+E86 (cf. D. Markowitz et al., J. Virol. 62, 1120-1124 (1988)) was used as the packaging cell.
The test was performed as follows:
F/L-HERc cells were cultivated in RPMI/1640 medium (BioWhittaker), supplemented with 10% fetal calf serum (FCS, Boehringer Mannheim), 2 mM glutamine (BioWhittaker), standard antibiotics and 20 ng/ml of human EGF (Promega), at 37xc2x0 C. and 5% CO2. In order to investigate the inhibitory activity of the compounds according to the invention, 1.5xc3x97104 cells per well were cultivated in triplicate in 96-well dishes in the above medium (200 xcexcl), the cell proliferation being stimulated with either EGF (20 ng/ml) or murine IL-3. The IL-3 used was obtained from culture supernatants of the cell line X63/0 mIL-3 (cf. H. Karasuyama et al., Eur. J. Immunol. 18, 97-104 (1988)). The compounds according to the invention were dissolved in 100% dimethylsulfoxide (DMSO) and added to the cultures in various dilutions, the maximum DMSO concentration being 1%. The cultures were incubated for 48 hours at 37xc2x0 C.
In order to determine the inhibitory activity of the compounds according to the invention the relative cell number was measured in O.D. units using the Cell Titer 96(trademark) AQueous Non-Radioactive Cell Proliferation Assay (Promega). The relative cell number was calculated as a percentage of the control (F/LHERc cells without inhibitor) and the concentration of active substance which inhibits the proliferation of the cells by 50% (IC50) was derived therefrom. The following results were obtained:
The compounds of general formula I according to the invention thus inhibit the signal transduction by tyrosine kinases, as demonstrated by the example of the human EGF receptor, and are therefore useful for treating pathophysiological processes caused by hyperfunction of tyrosine kinases. These are, e.g., benign or malignant tumors, particularly tumors of epithelial and neuroepithelial origin, metastasization and the abnormal proliferation of vascular endothelial cells (neoangiogenesis).
The compounds according to the invention are also useful for preventing and treating diseases of the airways and lungs which are accompanied by increased or altered production of mucus caused by stimulation of tyrosine kinases, e.g., in inflammatory diseases of the airways such as chronic bronchitis, chronic obstructive bronchitis, asthma, bronchiectasias, allergic or non-allergic rhinitis or sinusitis, cystic fibrosis, xcex11-antitrypsin deficiency, or coughs, pulmonary emphysema, pulmonary fibrosis, and hyperreactive airways.
The compounds are also suitable for treating diseases of the gastrointestinal tract and bile duct and gall bladder which are associated with disrupted activity of the tyrosine kinases, such as may be found, e.g., in chronic inflammatory changes such as cholecystitis, Crohn""s disease, ulcerative colitis, and ulcers in the gastrointestinal tract or such as may occur in diseases of the gastrointestinal tract which are associated with increased secretions, such as Mxc3xa9netrixc3xa9r""s disease, secreting adenomas and protein loss syndrome. The compounds are also suitable for treating nasal polyps and polyps of the gastrointestinal tract of various origins, such as, for example, villous or adenomatous polyps of the large bowel, but also polyps in familial polyposis coli, intestinal polyps in Gardner""s syndrome, polyps throughout the entire gastrointestinal tract in Peutz-Jeghers Syndrome, inflammatory pseudopolyps, juvenile polyps, colitis cystica profunda, and pneumatosis cystoides intestinales.
Moreover, the compounds of general formula I and the physiologically acceptable salts thereof may be used to treat kidney diseases, particularly cystic changes as in cystic kidneys, for treating renal cysts which may be idiopathic in origin or which occur in syndromes such as, e.g., tubercular sclerosis, in von-Hippel-Lindau Syndrome, in nephronophthisis and spongy kidney and other diseases caused by abnormal functioning of tyrosine kinases such as, e.g., epidermal hyperproliferation (psoriasis), inflammatory processes, diseases of the immune system, hyperproliferation of hematopoietic cells, etc.
By reason of their biological properties the compounds according to the invention may be used on their own or in conjunction with other pharmacologically active compounds, for example in tumour therapy, in monotherapy or in conjunction with other anti-tumour therapeutic agents, for example in combination with topoisomerase inhibitors (e.g., etoposide), mitosis inhibitors (e.g., vinblastine), compounds which interact with nucleic acids (e.g., cis-platin, cyclophosphamide, adriamycin), hormone antagonists (e.g., tamoxifen), inhibitors of metabolic processes (e.g., 5-FU etc.), cytokines (e.g., interferons), antibodies, etc. For treating respiratory tract diseases, these compounds may be used on their own or in conjunction with other therapeutic agents for the airways, such as substances with a secretolytic, broncholytic and/or anti-inflammatory activity. For treating diseases in the region of the gastrointestinal tract, these compounds may also be administered on their own or in conjunction with substances having an effect on motility or secretion or with anti-inflammatory substances. These combinations may be administered either simultaneously or sequentially.
These compounds may be administered either on their own or in conjunction with other active substances by intravenous, subcutaneous, intramuscular, intrarectal, intraperitoneal, or intranasal route, by inhalation or transdermally or orally, whilst aerosol formulations are particularly suitable for inhalation.
For pharmaceutical use the compounds according to the invention are generally used for warm-blooded vertebrates, particularly humans, in doses of 0.01-100 mg/kg of body weight, preferably 0.1-15 mg/kg. For administration they are formulated with one or more conventional inert carriers and/or diluents, e.g., with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethyleneglycol, propyleneglycol, stearyl alcohol, carboxymethylcellulose, or fatty substances such as hard fat or suitable mixtures thereof in conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions, solutions, sprays, or suppositories.
The following Examples are intended to illustrate the present invention without restricting it.